Safety and Efficacy of Catheter-directed Thrombolysis

Background

Catheter-directed thrombolysis (CDT) can be used as immediate thrombus removal, especially in the treatment for acute iliofemoral deep venous thrombosis (DVT). The rationale for CDT is to avoid morbidity in a post-thrombotic syndrome (PTS) by increasing venous patency, preventing damage of the venous valves and reflux. However, no consensus exists in this area because of lack of convincing evidence from randomized controlled trials. Additionally, controversies exist regarding the increased risk of pulmonary embolism (PE) and bleeding complications connected to this treatment modality. However, in the latest evidence-based clinical guidelines from the American College of Chest Physicians from 2008 early intervention for DVT using CDT or pharmacomechanical thrombolysis was recommended at a level 2B and 2C, respectively. ¹ Today, the use of CDT is restricted to only some centres.

Since CDT is a relatively new treatment, it has to be safe and effective. The previously used systemic thrombolysis was associated with an increased risk of bleeding complications and was not found to be as effective as intrathrombus catheter delivery in a randomized trial in the arterial system. ² Earlier, venous thrombectomy under general anaesthesia did not show clearly improved outcome compared with conventional anticoagulation therapy. ³ The method was associated with complications and a relatively high risk of re-thrombosis since it was not combined with additional stenting of the iliac stenosis. However, newer studies have combined venous thrombectomy with perioperative stenting with promising results. ⁴

DVT damage

The development of PTS is believed to be a consequence of ambulatory venous hypertension caused by venous valve incompetence and persistent luminal obstruction. The venous valves and the vein wall are believed to be damaged by inflammatory mediators associated with the presence of the acute thrombus or during the healing process with thrombus remodelling. In this process, leukocytes are activated with adhesion and migration through the basement membrane. ⁵ The transmission of the high deep venous pressure to the venous end of subcutaneous capillaries results in increased endothelial permeability and impaired capillary flow. The escape of large molecules into the interstitial tissue may explain the presence of interstitial oedema, hyper pigmentation and ulcer formation. ⁶ Observations indicate that the most severe post-thrombotic morbidity is associated with the highest venous pressures seen in patients with both venous obstruction and venous valve incompetence. ⁷ These patients have a higher risk of skin damage. ⁸

In a large study, several parameters that predicted the worst post-thrombotic morbidity were severity of venous symptoms at one month, iliofemoral thrombosis, previous ipsilateral thrombosis, female gender, older age and high body mass index, and iliofemoral location has been found to predispose to PTS more frequently than infrainguinal DVT. ⁹ Iliofemoral DVT predisposes patients to higher recurrence rates compared with infrainguinal DVT ¹⁰ and development of recurrent ipsilateral thrombosis has in several studies been found to be strongly associated with the risk for PTS. ¹¹

Action of thrombolysis

The delivery of the thrombolytic agent (streptokinase, urokinase or tissue plasminogen activator [t-PA]) directly into the venous clot (high intrathrombus drug concentration) accelerates thrombolysis by converting the fibrin-bound plasminogen into the active enzyme plasmin thereby dissolving the clot. In this way a systemic influence is assumed to be minimized, thereby reducing the risk of complications for the patient. Unfractionated heparin is added to the lytic fluid. Today t-PA is the mostly used drug, due to short half-life, given as a minimum of 1 mg per hour with heparin adjusted in order to keep the activated partial thromboplastin time (APTT) on a level of maximum 100 seconds. This chemical action can be monitored clinically but more accurate by daily biochemical surveillance. The patients reveal symptom relief as soon as the thrombus load is reduced. Contraindications to CDT have been described in a previous publication from 2010. ¹²

DVT age prior to CDT

Before the patient is treated with CDT, a thorough anamnesis has to be obtained. Questions about the exact duration of symptoms, the cause or predisposing factor, previous episodes of DVT, information about thrombophilia, etc. should be covered. A very important issue connected to this treatment modality is the duration of symptoms, as the best results are seen when treating acute thrombosis supported by results from a multicentre registry from 1999. ¹³ Acute DVT refers to venous thrombosis for which symptoms have been present for a maximum of 14 days or for which diagnostic imaging indicates that venous thrombosis occurred within the last 14 days. ¹⁴ Longer duration of symptoms will influence the results negatively. ¹⁵ Do not stop with contraceptive pills before treatment.

Technique

Often the popliteal vein is used for insertion of guide wires for the procedure. ¹² The vein is accessed using micropuncture technique under ultrasound (US) guidance in order to avoid multiple punctures and a subsequent risk of bleeding. Fluoroscopy is helping to steer the wire in an intrathrombus position followed by a multi-side-hole catheter with tip occlusion. A venogram is made to map the precise extent of the thrombus. The precise composition of the thrombolytic fluid and volume injected per hour has been described in detail previously. ¹²

Some studies describe the use of the posterior tibial or sural vein approach in cases of popliteal or calf vein thrombosis.^13,16 In our department, infusion of the thrombolytic agent is done using the pulse-spray technique in almost all cases. Venography is used to evaluate thrombolysis and is performed every 24 hours.

As patients are immobilized during treatment, the calf muscle pump is compromised and therefore an intermittent pneumatic compression device (IPC) is used in order to encourage maximal antegrade flow from the ankle through the previously thrombosed vein. The fluctuations of D-dimer during the treatment are very useful. The level will rise soon after thrombus resolution and CDT should continue at least some hours even though the level of D-dimer is almost normalized. These observations are done parallel to biplane venograms demonstrating fully lysed and patent vein segments (Figure 1). OPEN IN VIEWER

Vena cava filter

In some cases, the iliofemoral DVT extends into the inferior vena cava (IVC), and a prophylactic IVC filter can be inserted. The filter can be inserted from the contralateral femoral vein or from the jugular vein. One paper has described filter placement in all patients to prevent PE, ¹⁷ whereas others have used filters only in case of free floating thrombus in the IVC. ¹⁸ We have used retrievable filters only in cases of free floating thrombus in the IVC. ¹² However, the need for a filter is questionable.

Biochemistry

Haemostasis monitoring is performed by daily analysis of haemoglobin, fibrinogen, APTT, thrombin time, antithrombin and platelet count. The APTT is monitored to assess the effect of intravascular use of unfractionated heparin. A high level of APTT or decline in fibrinogen and haemoglobin has to be observed and thereby the dose lowered or the infusion temporarily stopped parallel to a careful search for bleeding.

Monitoring in the clinical ward

The nursing staff has a great responsibility for making the stay of the patient as safe as possible. The patients are lying flat with the head tilted 30–40 degrees without permission for the toilet. No bladder catheterization is used. This regimen will keep the thrombolysis catheter in the correct position. Once per eight hours dedicated nurses are controlling for bleeding, specifically from the puncture site, in the urine and from the vagina. Blood pressure, pulse and oxygen saturation is controlled. The doctors are responsible for mixing the correct dosages of the lytic fluid and for taking care of the infusion machine. Often, bleeding from the popliteal fossa leads to an extra compression bandage. Continuous bleeding episodes call for supplementary blood samples as previously mentioned. A psychological aspect shall not be forgotten, while these patients are often young and anxious for the outcome. This requires handling with repeated explanations and care of the patients and their families.

Definitions of complications

Complications can be described as major and minor. Major bleeding is defined as intracranial bleeding or bleeding severe enough to result in death, surgery, and cessation of therapy or blood transfusion. Minor bleeding is defined as less severe bleeding that can be managed with local compression, sheath upsizing, and/or dose alterations of the thrombolytic agent. PE can be seen at admission or can occur during the procedure due to thrombus manipulation. ¹⁴

Results from the Copenhagen experience

Almost 200 patients have been treated with CDT in the Vascular Clinic in Copenhagen so far. For this chapter we have looked more carefully into the rate and type of complications than appears from our previous publications and looked at the long-term results in the group of patients treated in the period 1999–2006. The basis for the results presented here is 89 patients, two patients treated bilaterally meaning 91 extremities with acute iliofemoral DVT.

The material consists of 70 women and 19 men with mean age of 29 years (range 14–57 years). All patients with a surgical or puerperal procedure (20 patients) waited a minimum of seven days before CDT. As expected a lot of risk factors are present in this category of patients with substantial overlap. Only a minor part of the material could not be identified as having any obvious reason (Tables 1 and 2).

One patient needed blood transfusion and one patient had a fasciotomy in the forearm due to bleeding from an arterial puncture site (performed before admission) (Table 3). Other bleeding episodes could be managed with local compression in the popliteal fossa or temporary reduction of t-PA or heparin steered by fibrinogen and APTT. In a review from 2009 reporting on 11 studies with a total of 979 lower limbs major bleeding was observed in 1–11% and minor bleeding complications were seen in up to 18%. ¹⁹ The number of 27% in our study correlates to a rather careful search for minor bleeding rather than a substantial risk or danger (Table 3).

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Table 1

Risk factors in 89 patients with acute iliofemoral deep venous thrombosis treated with catheter-directed thrombolysis

Type	Number of patients
Compression syndrome	54
Thrombophilia	48
Contraceptive pills	35
Puerperal	15
Surgery	5
Cancer	1

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Table 2

The patients classified according to the number of risk factors

Number of risk factor/patient	Percentage
0	11
1	38
2	36
3	15
Total	100

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Table 3

Complications associated with catheter-directed thrombolysis in 89 patients (91 extremities), Copenhagen experience

Complications	Symptom/clinical sign	Percentage
Mortality		0
Major bleeding	Haematoma in the back Haematoma in the forearm	2 (2/89)
Minor bleeding types	Puncture site/popliteal fossa	26 (24/91)
	Haematuria	8 (7/89)
	Vaginal	3 (3/89)
	Epistaxis	1 (1/89)
Patients with minor bleeding		27 (24/89) *
PE during procedure One patient with cough	0 (negative scintigram)

PE, pulmonary embolism

^*Some patients had more than one type of minor bleeding

Often the question concerning PE occurring during treatment has been raised. PE is a ‘none existing’ problem during CDT in our material. The clot disappearance is a dissolving process rather than a ‘clot fracture’ process. Another point is the fact that most iliofemoral DVT episodes are left-sided with an underlying compression syndrome in almost half of the cases thus preventing PE at least theoretically. Finally, we have inserted a retrievable cava filter in eight patients with a floating thrombus. Sometimes, the retrieved filter demonstrated thrombus inside, but this does not necessarily speak for a possible risk of PE. On the other hand, an empty filter can mean that clot material has been lysed by the t-PA. The low procedural occurrence of PE is already published many years ago.^13,16 Reports of only very few deaths directly related to CDT have been published. ¹³

Efficacy

The average time for CDT was 2 1/2 days. Stenting was performed in 54 procedures (61%). In five cases two stents were necessary to cover the obstructive lesion. A Wallstent was used in most cases. In three cases a procedural stent occlusion occurred with successful re-CDT in two patients supplemented with an extra stent in one case. At follow-up one patient had a stent-related occlusion without success after re-CDT Removal of a stent in another patient was done due to pain in the groin. Substitution with a polytetrafluoroethylene (PTFE) graft solved the problem.

The patients were followed yearly with US examination for patency in the supine position and valve sufficiency in a standing position. Retrograde flow >1/2 second was defined to be reflux in all vein segments except >1 second in the common femoral vein. The outcome for the treated limbs is seen as a Kaplan-Meier plot in Figure 2. The mean follow-up was 87 months (range 17–148 months). OPEN IN VIEWER

Patients had been kept on anticoagulation (AC) treatment along with recommendation for short compression stockings for two years. Lifelong AC treatment had been advocated strictly in almost 40% of the material due to prior PE, cava atresia and severe thrombophilia.

These results are based on the longest follow-up study presented in the literature, and the results are still at the same level compared with previous results from our group of patients with shorter mean follow-up. Concerning PTS judged from the Villata score we have published on 109 patients with a mean follow-up of 71 months demonstrating PTS in 16.5% of the patients with same technical success rate ²⁰ also reflecting greater quality of life (QOL) in patients with competent veins compared with those with valve insufficiency and/or chronic occlusion.

Recommendations

Conclusion

CDT is a safe treatment modality performed under conditions with simple biochemical monitoring and careful nursing in a clinical ward without any reported mortality in the last decennium directly related to CDT. The complications are minor concerning bleeding, and PE almost does not exist. Using standards for the technical aspects of the procedure, the real long-term efficacy is demonstrated being on a high level. Randomized controlled trials appearing in some years will hopefully support the initial reports by significantly preventing PTS.

Declaration: The authors declare no conflicts of interest.